LMAN1 mutations in colorectal cancer development Abstract Every year over 50,000 people die of colorectal cancer, making it the third most common cause of cancer death in the United States. Identification and functional characterization of new pathways associated with oncogenes and tumor suppressor genes are important in understanding the disease mechanism and the development of targeted treatment approaches. A recent report identified frequent biallelic mutations that result in the loss of LMAN1 expression in microsatellite unstable (MSI-H) adenomas and carcinomas, suggesting that LMAN1 mutations occur early in tumor development and are positively selected in MSI-H colorectal tumors. Our group has shown that LMAN1 is a mannose-binding lectin that functions as a cargo receptor for the transport of glycoproteins from the endoplasmic reticulum (ER) to the Golgi. To determine whether LMAN1 mutations contribute to tumor development, we tested LMAN1 expression in human microsatellite stable (MSS) colorectal cancer tissues, and found complete or partial loss of LMAN1 expression in 40% of them. Using mouse models and colorectal cancer cell lines that are deficient in LMAN1 expression, we have obtained strong preliminary data suggesting that LMAN1 functions as a novel suppressor of colorectal cancer. Initial studies of 65 MSS colorectal cancer patients revealed that those lacking LMAN1 expression had significantly worse prognosis than those with normal LMAN1 expression. The specific aims of this proposal are: 1) to elucidate the molecular mechanism by which LMAN1 deficiency contributes to formation and development of colorectal cancers; 2) to identify the underlying mechanisms for the loss of LMAN1 expression in human MSS colorectal cancer tissues. This study will uncover previously unknown links between protein secretory deficiency and carcinogenesis in the colorectal cancer suppression by LMAN1. Results may lead to effective personalized medical care for a subset of patients whose cancer is deficient in LMAN1. Knowledge gained from these studies may be applicable to other types of cancer.